Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids

Definitions

• the present invention relates to therapeutic applications in humans and animals of the p-chlorophenyl ester of p-chlorophenoxyisobutyric acid.
• esters and salts of clofibric acid and, in particular, the ethyl ester (clofibrate), the 3-dimethylcarbamoylpropyl ester (clofibride), and the aluminum, calcium and pyridoxine salts are used in therapy.
• the p-chlorophenyl ester shows a very low toxicity and a hypolipidemic activity superior to that of clofibric acid and nicotinic acid.
• the p-chlorophenyl ester of clofibric acid is a known chemical product (M. Julia et al, Bull. Soc. Chim. France, 1956, 776-83). Nevertheless, the therapeutic applications of this product have never before been described.
• hypolipidemic agents Both clofibric acid and nicotinic acid have been used as hypolipidemic agents, however a need continues to exist for hypolipidemic agents having even lower toxicity and higher activity than the above.
• one object of the invention is to provide a hypolipidemic composition of low toxicity.
• Another object of the invention is to provide a method of lowering serum lipid levels.
• hypolipidemic composition which comprises p-chlorophenyl 2-(p-chlorophenoxy)-2-methylpropionate, as principal active ingredient, in combination with a pharmaceutically acceptable carrier; and a method of reducing serum lipid levels in humans or animals which comprises administering a hypolipidemically effective amount of p-chlorophenyl 2-(p-chlorophenoxy)-2-methylpropionate.
• the present inventors have now discovered that the p-chlorophenyl ester of clofibric acid shows a very low toxicity and a hypolipidemic activity significantly superior to that of both clofibric acid and nicotinic acid for reducing both total serum lipid levels and serum cholesterol levels.
• This ester may be performed according to classical methods.
• One example of this preparation is the following.
• the NMR spectrum is CDCl 3 (internal reference, TMS) shows a singlet centered at 1.7 ppm corresponding to the 6 methyl protons and a complex multiplet at 6.7-7.4 ppm corresponding to 8 aromatic protons.
• the acute toxicity of the p-chlorophenyl ester of clofibric acid was determined using two species of animals (Swiss EOPS mice and Wistar EOPS rats) by oral administration, the product being administered in a gum preparation. The animals were observed during 14 days. For the mice, a dose of 2000 mg/kg resulted in 10% mortality. For the rat, a dose of 2000 mg/kg did not result in any mortality, whereas the same dose of clofibric acid resulted in 40% mortality.
• hypolipidemic activity was determined in rats subjected to a regimen rich in lipids over the course of 2 sets of experiments.
• mice Male Wistar EOPS rats weighing in the neighborhood of 140 g receive a regimen rich in lipids during 21 days. Beginning with the eleventh day, the animals receive either a gum preparation containing the product to be tested or a preparation of 6% gum arabic alone, for 6 days out of 7. After the last feeding, and a subsequent 24 hour fast, the animals are sacrificed. A group of animals submitted to a normal regimen is used as a control. The results are present in Table II. The percentage reductions of lipid levels are calculated using the following equation: ##EQU2##
• the p-chlorophenyl ester reduces serum lipid and cholesterol levels to a greater degree than the acid. These differences are significant.
• the weight of the animals' livers increases using the p-chorophenyl ester but at equivalent dosage levels, the increase in weight is smaller than when the acid is used, and this difference is statistically significant.
• a subchronic toxicity study of the p-chlorophenyl ester of clofibric acid was carried out using the following protocol.
• the product was administered six days a week during the course of a month, by oral administration in a gum preparation, to male Wistar EOPS rats having an average initial weight of 200 g. After the last feeding, the animals were fasted. A blood sample is taken from the abdominal aorta under anesthesia, then the animals are sacrificed. Table III shows the results of sampling the blood levels.
• the notation NS or S signifies whether the change induced by the product to be tested was statistically nonsignificant or significant.
• the p-chlorophenyl ester of p-chlorophenoxyisobutyric acid is therapeutically useful for treatment of lipid disfunction (hypercholesterolemia with or without xanthomatosis, hypertriglyceridemia, combined hyperlipidemia) as well as atherosclerotic conditions such as coronary insufficiency, cerebral vascular conditions, arteritis of inferior members, and arterial hypertension.
• the active principle may be administered in association with appropriate vehicles and in various pharmaceutically acceptable forms, for example by oral administration in unit dosage form such as gels, capsules, tablets and lozenges at a dose of 0.1 to 2.5 g per day in 2 to 4 administrations per day.

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Emergency Medicine (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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Publications (1)

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• 1977
  • 1977-03-08 FR FR7706689A patent/FR2382892A1/fr active Granted
• 1978
  • 1978-02-25 DE DE2808203A patent/DE2808203C2/de not_active Expired
  • 1978-03-01 CH CH220678A patent/CH628243A5/fr not_active IP Right Cessation
  • 1978-03-06 BE BE185696A patent/BE864601A/xx not_active IP Right Cessation
  • 1978-03-07 PT PT67753A patent/PT67753A/pt not_active IP Right Cessation
  • 1978-03-07 NL NL7802474A patent/NL7802474A/xx not_active Application Discontinuation
  • 1978-03-08 US US05/884,497 patent/US4179519A/en not_active Expired - Lifetime

Non-Patent Citations (2)

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